Dental composition for hypersensitive teeth

ABSTRACT

The invention relates to an oral composition for the treatment and prevention of dental hypersensitivity comprising an anti-hypersensitivity agent embedded in a sustained release carrier such as a cellulosic or hydrophobic polymer, and a method for the use of said composition in treating and preventing dental hypersensitivity. The invention also provides for the supplementation of said oral composition with an adhesive and a plasticizer to increase the effectiveness of the anti-hypersensitivity agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 07/898,096, filed Jun.12, 1992, now U.S. Pat. No. 5,403,577, which is a continuation of Ser.No. 07/662,985, filed Feb. 28, 1991, now U.S. Pat. No. 5,139,768, whichis a continuation of Ser. No. 07/532,328, filed Jun. 5, 1990, abandoned,which is a continuation-in-part of Ser. No. 07/304,091, filed Jan. 31,1989, abandoned.

FIELD OF THE INVENTION

The invention is directed to a dental composition for preventinghypersensitivity in teeth, and to a method for the use of suchcomposition for the treatment of hypersensitive teeth.

BACKGROUND OF THE INVENTION

Dental hypersensitivity, especially that arising from dentin andcementum hypersensitivity, is a frequently encountered problem indentistry and a very troublesome clinical complaint. Hypersensitivitymay occur wherever the dentin or cementum of a tooth is exposed byattrition or abrasion, or when the tooth's fine root surface is exposedby periodontal disease. In about 12% of erupted teeth, there is adevelopmental lack of protective covering of cementum at thecementoenamel junction. As a result, when the exposed dentin issubjected to mechanical, thermal, chemical or osmotic stimuli, thesensory nerves of the teeth become excited and a very painful responseresults. For example, people with hypersensitive teeth find it verypainful to orally ingest certain forms of nourishment, such as liquidsor foods that are hot or cold, sweet, hypertonic or contain citric acid.Everyday stimuli such as brushing the teeth may also be painful.

Many attempts have been made to control hypersensitivity of the teeth.For example, U.S. Pat. No. 3,863,006 (Hodosh, M.) describes the use ofpotassium, lithium or sodium nitrate; U.S. Pat. No. 4,751,072 and U.S.Pat. No. 4,631,185 (both to Kim, S.) describe the use of potassiumbicarbonate and potassium chloride; U.S. Pat. No. 4,710,372 and U.S.Pat. No. 4,634,589 ( both to Scheller, H. U.) describe the use ofhydroxyapatite or fluorapatite; U.S. Pat. No. 4,057,621 Pashley, D. H.,et al.) describes the use of an alkali metal or ammonium oxalate; U.S.Pat. No. 4,415,549 (Shah, N. B.) describes the use of strontium EDTA,fluoride and ammonium glycyrrhizzinate; and, GB990957 (Rosenthal, M. W.)describes the use of strontium for the control of hypersensitivity. Theuse of strontium ions to treat hypersensitivity was also disclosed inU.S. Pat. Nos. 3,122,483, 3,988,434 and 4,224,310.

However, although clinically the most effective for reducing toothhypersensitivity, the use of strontium salts for the treatment ofhypersensitivity is disliked by patients due to the tendency ofstrontium salts to leave an unacceptably salty taste or metallic tastein the mouth, even when used in a toothpaste form. Another majordisadvantage of strontium dentifrice is the long period of time ofapplication which is required to achieve the clinical effect.

A topical, sustained-release form of an agent capable of controllingdental hypersensitivity could help prevent undesirable taste sideeffects and still treat the hypersensitive condition. Such a dosage formwould be able to release the agent controlling the hypersensitivity at alower therapeutic level over a long period of time, for example, forweeks. Sustained localized release of the hypersensitivity agent,targeted directly to the hypersensitive site, would also solve theproblem of the prolonged time and application currently required toobtain clinical effectiveness with strontium.

Sustained release of an agent to treat a dental disease, peridontaldisease, has been reported to be achieved by embedding chlorhexidine inan ethyl cellulose polymer to form a varnish (Friedman, M., et al., J.Perio. Res. 17:323-328 (1982); Friedman, M., et al., IADR Prog. andAbstr. 59:No. 905 (1980); Soskolne, W. A., et al., J. Perio. Res.18:330-336 (1983)). This dosage form was also used in the treatment ofplaque prevention in patients wearing orthodontic appliances (Friedman,M., et al., J. Dent. Res. 64:1319-1321 (1985)). However, this treatment,termed a varnish because it is applied to the surface of the teeth ortissues, was not deemed useful for the long-term prevention of thedental condition. Thus a need exists for the identification of a varnishcomposition capable of supplying a dental agent in an efficacioussustained-release, long term dosage form.

Wahmi (U.S. Pat. No. 4,374,824) discloses dentifrices for cleaning andpreserving teeth. Disclosed were compositions comprising ginger,magnesium silicate, sodium chloride, catechu, alum, seed and shell ofsweet almond, pyrethrum, gum mastic, and tobacco. It was reported thatgum mastic was added to the composition to assist in the prevention oftooth decay. The disclosed compositions were intended to be in the formof toothpaste or tooth powders. The Wahmi patent does not disclose thepossible long-term anti-hypersensitivity effect of the compositions;further, application of the disclosed compositions two to three timesper day is required for antiplaque activity.

Mastic has been used previously for other dental purposes. U.S. Pat. No.4,668,188 (Wolfenson, G. B.) discloses the use of a curable mastic inthe production of an oral impression tray for making impressions ofteeth and jaw structures. Mastics have been used in the production ofdental molds (U.S. Pat. No. 4,500,288, VonWeissenfluh, H.) and as anadhesive to secure dental articulators (U.S. Pat. Nos. 4,548,581 and4,382,787, Hoffman, R. E.). U.S. Pat. Nos. 4,532,126 and 4,428,927(Ebert, W. R., et al.) disclose chewable, filled, one-piece soft elasticgelatin capsules, made chewable by a masticatory substance, such as asynthetic mastic.

U.S. Pat. No. 4,459,277 (Kosti, C. M.) relates to novel plaquecompositions for use in evaluating oral hygiene practices. In brief, thepatent discloses a water-insoluble, water-immiscible dye emulsified infine droplets or rupturable capsules. The patent discloses the use ofmastic resin as well as alginates, and other gums as an insoluble mediafor dye dispersion. In particular, sodium carboxymethylcellulose isdisclosed. Also disclosed is the possibility of incorporatingantibacterial agents such as stannous fluoride into the compositions.Significantly, the Kosti patent is concerned with diagnostic rather thantherapeutic applications. The patent fails to suggest compositionsexhibiting long-term preventive activity for hypersensitive teeth.

The background art fails to identify any compositions of mattercomprising an effective anti-hypersensitivity agent together with a longterm sustained release carrier capable of providing efficacious levelsof the anti-hypersensitivity agent, either alone or in combination withan adhesive polymer such as a mastic and a plasticizer such aspolyethylene glycol, for use as a hypersensitivity preventative byhumans and other animals, under conditions in which theanti-hypersensitivity agents have no undersirable side effects such aschanges in taste sensations.

SUMMARY OF THE INVENTION

With this need in mind, the present inventor set out to find ananti-hypersensitivity composition capable of delivering efficaciouslevels of an agent effective against those dental conditions responsiblefor hypersensitivity, said composition being such that the activeanti-hypersensitivity agent is released in a sustained, long-termfashion, without a salty or metallic taste, and such that thehypersensitivity composition has the property of long-term adhesion tothe teeth, and such that the hypersensitivity composition remainsplastic during the entire period of application. With this goal in mind,the inventor has discovered a hypersensitivity composition with thesedesirable characteristics using materials already approved by theF.D.A., the composition comprising a metal salt or otherhypersensitivity agent embedded in a sustained release carrier composedof a cellulose or hydrophobic polymer, in a pharmaceutically acceptablevehicle, optionally containing a plasticizer such as polyethylene glycoland/or an adhesive polymer such as gum mastic.

The invention is further directed to a sustained-release dentalhypersensitivity preventative varnish composition which comprises: (a)an agent capable of suppressing dental hypersensitivity, and (b) asustained release ethyl cellulose or hydrophobic polymer, in apharmaceutically acceptable vehicle, wherein such composition is capableof forming a film which adheres to a dental surface, and wherein suchfilm which adheres to a dental surface is capable of providingefficacious levels of such agent for the treatment of such dentalhypersensitivity for a suitable period of time.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to oral compositions that provide sustained,efficient, inexpensive, anti-hypersensitivity activity withoutdeleterious or undesirable side effects, and methods for using suchcompositions.

By "sustained-release" is meant the continuous release of an activesubstance at efficacious levels for a suitable period of time, such asovernight. By a "suitable" period of time is meant a period of timesufficiently long to provide the desired treatment for hypersensitivity.The release of the active substance may be constant or pulsed, as longas efficacious levels of the active substance are provided to thesurrounding milieu for the desired period of time.

By an "efficacious level" is meant a level or concentration of a drug orother active agent which is high enough to be effective in treating thecondition the drug was designed to treat.

By "oral varnish" is meant a composition which is topically applied to asurface such as a tooth, and which dries as a film adhering to thatsurface, in a manner which resists removal under normal conditions, forexample by saliva and unvoluntary mouth movements during sleep, and ismechanically removable, for example by brushing the teeth.

The compilation of the components of the aforementioned oral compositionis based upon the specific properties of each of the individualcomponents, wherein each component of the combination increases theantihypersensivity effectiveness of other members of the combination.

The oral composition of the invention assists in the prevention ofdental hypersensitivity. A variety of anti-hypersensitivity agents aresuitable for the present invention. Preferred is the use of strontiumsalts. Other anti-hypersensitivity agents useful in the composition ofthe invention include potassium, lithium or sodium nitrate, potassiumbicarbonate, potassium chloride, hydroxyapatite, fluorapatite, ammoniumoxalate, EDTA with fluoride, fluoride, and ammonium glycyrrhizzinate.

It is also a feature of this invention that the aforementionedanti-hypersensitivity agent is released to the hypersensitive site in along-term sustained release manner so as to reduce the requiredfrequency of use. This kind of release is accomplished by embedding theanti-hypersensitivity agent in a cellulosic or hydrophobic acrylicpolymer to form a varnish for administration to the oral cavity. The useof these polymers has the additional advantage of minimizing sideeffects of the hypersensitivity agent. Preferred are the insoluble andinexpensive polymers: hydrophobic type (polyethylene, polymethacrylate,polyamide-nylon, poly(ethylene-vinyl acetate) cellulose nitrate,silicones and others). A preferred cellulosic polymer is ethylcellulose.

Thus, in a preferred embodiment, an oral composition with the highlydesirable characteristics mentioned above comprises ananti-hypersensitivity compound such as strontium, preferably strontiumchloride, embedded in a sustained release cellulosic polymer such asethyl cellulose, in a pharmaceutically effective vehicle. For example,strontium (1-5 parts) and ethyl cellulose (5-9 parts) may be dissolvedin ethanol (80-120 parts) for the preparation of sustained releasedelivery systems. The efficacy of such preparations (see examples below)demonstrates that the anti-hypersensitivity agent is efficientlyreleased from said varnish at efficacious levels for an overnightperiod. In another embodiment, combinations of strontium salts withanother anti-hypersensitive agent are used.

For application to a dental surface, that is, a surface within the oralcavity such as the buccal and lingual surfaces of teeth, an ethanolicsolution of the antisensitivity agent and cellulosic or hydrophobicpolymer (containing up to 4% of the anti-hypersensitivity agent as usedin the varnish) are applied with a soft brush or with a spray. The dryfilm is formed in situ, after application of the varnish to the toothsurface and evaporation of the solvent. Mouthwash forms are not suitablebecause of inefficient application of the composition to affected areas.Preferably, a film of 10-160 μm thick dries on the surface of the tooth.

Those skilled in the art of oral medicine will, without undueexperimentation, be able to produce ranges of concentrations of otherappropriate antisensitivity agents and sustained release polymers.

It is another feature of the invention that the oral compositions forhypersensitivity treatment and prevention also provide for additionaldesirable components. For example, the adhesiveness of the oralcomposition may be improved by the incorporation within said compositionof gums such as gum mastic in a formulation providing from 1-20% byweight of the gum mastic. Other suitable mastics are disclosed in U.S.Pat. No. 4,315,779 to Heyd, D., et al., and U.S. Pat. No. 4,374,844 toWahmi, H. V. R., et al.

In another formulation, other compositions may includedemulcents/humectants (i.e., plasticizers) such as polyethylene glycol400-4000, glycerol, sorbitol, or mineral oil in concentrations of about1% by weight. Other humectants, detergents, or surface-active agentswill be known to those skilled in the formulation of oral compositions.

Thus, in a preferred composition, the oral composition of the inventioncomprises strontium, ethyl cellulose polymer, an adhesive, aplasticizer, and solvent (i.e., aqueous ethanol). In a highly preferredformulation, gum mastic is also present. Water, flavorings, and coloringagents may also be present as required.

Having now generally described the invention, the same will becomebetter understood by reference to certain specific examples which areincluded herein for purposes of illustration only and are not intendedto be limiting unless otherwise specified.

EXAMPLE 1 Varnish Preparation

The following formulations (Table 1) were all prepared by the samegeneral procedure as follows: ethyl cellulose and polyethylene glycolpolymers were dissolved in the suitable solvent. After completedissolution of the polymers, the additional components of the varnishwere added.

Ethyl cellulose--EC

Polyethylene glycol--PEG

Strontium chloride--STR

                                      TABLE 1                                     __________________________________________________________________________    MATERIAL/FORMULATION                                                                   I  II III                                                                              IV V  VI VII                                                                              VIII                                                                             IX                                           __________________________________________________________________________    STR (G)  1.0                                                                              2.0                                                                              3.0                                                                              3.0                                                                              3.0                                                                              4.0                                                                              3.0                                                                              3.0                                                                              3.0                                          EC-NF100 (G)                                                                           8.5                                                                              7.0                                                                              6.0                                                                              6.0                                                                              6.0                                                                              5.0                                                                              6.0                                                                              6.0                                                                              6.0                                          PEG 400 (G)                                                                            0.5                                                                              1.0                                                                              1.0                                                                              1.0                                                                              1.0                                                                              1.0                                                                              -- -- --                                           PEG 4000 (G)                                                                           -- -- -- -- -- -- 1.0                                                                              -- --                                           GLYCEROL (G)                                                                           -- -- -- -- -- -- -- 1.0                                                                              --                                           MINERAL OIL (G)                                                                        -- -- -- -- -- -- -- -- 1.0                                          ETHANOL (C"C)                                                                          100                                                                              100                                                                              100                                                                              80 120                                                                              100                                                                              100                                                                              100                                                                              100                                          __________________________________________________________________________

The best formulation was No. IV. The concentration of strontium in No.IV is lower than that currently used in toothpaste and dental solutionswhich contain 10% strontium.

The Effect of Local Application of Sustained Release Varnish ContainingStrontium on Hypersensitivity of Teeth

The effects of local application of a sustained-release delivery systemof strontium on hypersensitive teeth is shown in Table 2.

The study includes nine patients, among whom 55 teeth were treated.Patients applied to their teeth nightly the strontium varnishformulation No. IV from Table 1 and the teeth were tested again after 7and 30 days. Sensitivity was rated on a scale of 0-5, with five beingthe highest sensitivity. None of the patients complained of a metallicor salty taste.

                  TABLE 2                                                         ______________________________________                                        The effect of local application of sustained-release                          varnish of strcntium on hypersensitivity of teeth                             Mechanical stimuli  Thermal stimuli                                           day 0      day 7    day 30  day 0  day 7                                                                              day 30                                ______________________________________                                        Patient 1                                                                             4      2        2     5      4    3                                           1      0        0     4      3    1                                           3      3        2     3      1    0                                           3      1        1     3      2    2                                           2      1        0     3      1    0                                           1      1        0     1      1    0                                           4      3        2     4      4    1                                   Patient 2                                                                             2      2        1     4      2    2                                           4      3        4     5      5    4                                           3      2        2     3      2    2                                   Patient 3                                                                             5      4        3     5      4    4                                           3      3        3     2      2    1                                           3      3        2     2      2    1                                           4      3        0     5      4    3                                           1      1        0     2      2    1                                   Patient 4                                                                             3      2        1     4      3    0                                           1      1        0     3      3    2                                           3      1        0     3      1    1                                   Patient 5                                                                             5      4        3     5      3    3                                           3      2        2     3      2    2                                           3      2        2     4      4    3                                           3      2        1     2      2    1                                           3      3        1     3      3    1                                   Patient 6                                                                             3      1        1     5      4    2                                           4      2        1     5      5    4                                           4      3        1     5      5    5                                           2      1        1     2      1    1                                           4      2        1     4      2    1                                           4      3        2     4      4    2                                           2      2        0     1      0    1                                           4      3        2     5      5    5                                           2      1        0     3      3    3                                           4      3        3     4      3    2                                           3      2        3     4      4    3                                   Patient 7                                                                             2      2        2     4      4    3                                           1      1        1     4      3    3                                           4      4        4     5      5    5                                           5      5        4     5      4    4                                           4      4        2     3      3    4                                   Patient 8                                                                             4      3        1     5      4    2                                           3      3        1     4      3    3                                           3      3        0     5      3    3                                           3      3        1     4      2    2                                           3      3        1     5      5    2                                           5      4        2     5      5    5                                           3      2        1     4      2    1                                           3      2        1     4      4    4                                   Patient 9                                                                             2      0        0     3      2    1                                           1      0        0     4      3    2                                           3      1        0     5      4    3                                           1      0        0     4      3    3                                           2      1        1     4      3    2                                           2      1        1     5      5    2                                           2      2        1     3      3    3                                           3      1        2     4      4    4                                   Number: 55     55       55    55     55   55                                  Mean:   2.94   2.13     1.33  3.80   3.09 2.33                                Median: 3.00   2.00     1.00  4.00   3.00 2.00                                Standard                                                                              1.11   1.17     1.12  1.09   1.26 1.36                                Deviation:                                                                    ______________________________________                                    

Statistical Evaluation Mechanical Stimuli

Day 7--significantly different than day 0 (PL10⁻⁶, pair t-test,two-tailed).

Day 30--significantly different than day 0 (PL10⁻⁶, pair t-test,two-tailed).

Thermal Stimuli

Day 7--significantly different than day 0 (PL10⁻⁶, pair t-test,two-tailed).

Day 30--significantly different than day 0 (PL10⁻⁶, pair t-test,two-tailed).

The results in Table 2 show that most of the teeth varnished with astrontium-containing composition of the invention were no longerhypersensitive or showed significantly less hypersensitivity for as longas 30 days after beginning the application of the varnish on a dailybasis.

Now having fully described the invention, it will be understood by thosewith skill in the art that the scope may be performed with a wide andequivalent range of conditions, parameters, and the like, withoutaffecting the spirit or scope of the invention or any embodimentthereof.

What is claimed is:
 1. A sustained-release dental hypersensitivitypreventative varnish composition which comprises:(a) an agent capable ofsuppressing dental hypersensitivity; and (b) a sustained-release ethylcellulose or hydrophobic polymer completely dissolved in apharmaceutically acceptable solvent, wherein said sustained-releasehydrophobic polymer is selected from the group consisting ofpolyethylene, polyamide-nylon, poly(ethylene-vinyl acetate) cellulosenitrate and silicones, wherein said pharmaceutically acceptable solventcomprises a solvent selected from the group consisting of water, ethylalcohol, and a mixture of ethyl alcohol and water; and wherein saidcomposition forms a film which adheres to a dental surface upon removalof said solvent, and wherein said film which adheres to a dental surfaceis capable of providing efficacious levels of said agent for thetreatment of said dental hypersensitivity for a suitable period of time.2. The varnish composition of claim 1, wherein said agent capable ofsuppressing dental hypersensitivity is selected from the groupconsisting of a strontium salt, potassium, lithium or sodium nitrate,potassium bicarbonate, potassium chloride, hydroxyapatite, fluorapatite,ammonium oxalate, EDTA with fluoride, fluoride, and ammoniumglycyrrhizzinate.
 3. The varnish composition of claim 2, wherein saidagent capable of suppressing dental hypersensitivity is a strontiumsalt.
 4. A method of prevention of dental hypersensitivity comprisingtopical application of the varnish composition of claim 1 to the teethor gingival tissues of an animal.
 5. The varnish composition of claim 1,wherein said sustained release polymer is ethyl cellulose.
 6. The methodof claim 4, wherein said application is by brush.
 7. The varnishcomposition of claim 1, which additionally contains an agent selectedfrom the group consisting of a flavoring agent, surface active agent andcoloring agent.
 8. The varnish composition of claim 1, whichadditionally contains a plasticizer.
 9. The varnish composition of claim8, wherein said plasticizer is selected from the group consisting ofpolyethylene glycol, glycerol, sorbitol, and mineral oil.
 10. Thevarnish composition of claim 1, which additionally contains an adhesivegum.
 11. The varnish composition of claim 10, wherein said adhesive gumis gum mastic.
 12. The method of claim 4, wherein said application is byspray.
 13. The method of claim 4, wherein said animal is a human. 14.The method of claim 4, wherein said animal is a domesticated animal.